In silico Exploration of Interactions Between Potential COVID-19 Antiviral Treatments and the Pore of the hERG Potassium Channel—A Drug Antitarget

Background: In the absence of SARS-CoV-2 specific antiviral treatments, various repurposed pharmaceutical approaches are under investigation for the treatment of COVID-19. Antiviral drugs considered for this condition include atazanavir, remdesivir, lopinavir-ritonavir, and favipiravir. Whilst the combination of lopinavir and ritonavir has been previously linked to prolongation of the QTc interval on the ECG and risk of torsades de pointes arrhythmia, less is known in this regard about atazanavir, remdesivir, and favipiravir. Unwanted abnormalities of drug-induced QTc prolongation by diverse drugs are commonly mediated by a single cardiac anti-target, the hERG potassium channel. This computational modeling study was undertaken in order to explore the ability of these five drugs to interact with known determinants of drug binding to the hERG channel pore.Methods: Atazanavir, remdesivir, ritonavir, lopinavir and favipiravir were docked to in silico models of the pore domain of hERG, derived from cryo-EM structures of hERG and the closely related EAG channel.Results: Atazanavir was readily accommodated in the open hERG channel pore in proximity to the S6 Y652 and F656 residues, consistent with published experimental data implicating these aromatic residues in atazanavir binding to the channel. Lopinavir, ritonavir, and remdesivir were also accommodated in the open channel, making contacts in a model-dependent fashion with S6 aromatic residues and with residues at the base of the selectivity filter/pore helix. The ability of remdesivir (at 30 μM) to inhibit the channel was confirmed using patch-clamp recording. None of these four drugs could be accommodated in the closed channel structure. Favipiravir, a much smaller molecule, was able to fit within the closed channel and could adopt multiple binding poses in the open channel, but with few simultaneous interactions with key binding residues. Only favipiravir and remdesivir showed the potential to interact with lateral pockets below the selectivity filter of the channel.Conclusions: All the antiviral drugs studied here can, in principle, interact with components of the hERG potassium channel canonical binding site, but are likely to differ in their ability to access lateral binding pockets. Favipiravir's small size and relatively paucity of simultaneous interactions may confer reduced hERG liability compared to the other drugs. Experimental structure-function studies are now warranted to validate these observations.

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New Insights on the Voltage Dependence of the KCa3.1 Channel Block by Internal TBA

The Journal of General Physiology ◽

10.1085/jgp.200409145 ◽

2004 ◽

Vol 124 (4) ◽

pp. 333-348 ◽

Cited By ~ 8

Author(s):

Umberto Banderali ◽

Hélène Klein ◽

Line Garneau ◽

Manuel Simoes ◽

Lucie Parent ◽

...

Keyword(s):

Transmembrane Potential ◽

Voltage Dependence ◽

Selectivity Filter ◽

Channel Structure ◽

Potential Profile ◽

Ammonium Ion ◽

Channel Pore ◽

Internal Medium ◽

K Concentration ◽

External K

We present in this work a structural model of the open IKCa (KCa3.1) channel derived by homology modeling from the MthK channel structure, and used this model to compute the transmembrane potential profile along the channel pore. This analysis showed that the selectivity filter and the region extending from the channel inner cavity to the internal medium should respectively account for 81% and 16% of the transmembrane potential difference. We found however that the voltage dependence of the IKCa block by the quaternary ammonium ion TBA applied internally is compatible with an apparent electrical distance δ of 0.49 ± 0.02 (n = 6) for negative potentials. To reconcile this observation with the electrostatic potential profile predicted for the channel pore, we modeled the IKCa block by TBA assuming that the voltage dependence of the block is governed by both the difference in potential between the channel cavity and the internal medium, and the potential profile along the selectivity filter region through an effect on the filter ion occupancy states. The resulting model predicts that δ should be voltage dependent, being larger at negative than positive potentials. The model also indicates that raising the internal K+ concentration should decrease the value of δ measured at negative potentials independently of the external K+ concentration, whereas raising the external K+ concentration should minimally affect δ for concentrations >50 mM. All these predictions are born out by our current experimental results. Finally, we found that the substitutions V275C and V275A increased the voltage sensitivity of the TBA block, suggesting that TBA could move further into the pore, thus leading to stronger interactions between TBA and the ions in the selectivity filter. Globally, these results support a model whereby the voltage dependence of the TBA block in IKCa is mainly governed by the voltage dependence of the ion occupancy states of the selectivity filter.

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Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking

Biochemical Pharmacology ◽

10.1016/j.bcp.2016.05.013 ◽

2016 ◽

Vol 113 ◽

pp. 24-35 ◽

Cited By ~ 18

Author(s):

Yihong Zhang ◽

Charlotte K. Colenso ◽

Aziza El Harchi ◽

Hongwei Cheng ◽

Harry J. Witchel ◽

...

Keyword(s):

Potassium Channel ◽

In Silico ◽

Channel Pore ◽

In Silico Docking

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Functional Consequences of a Decreased Potassium Affinity in a Potassium Channel Pore

The Journal of General Physiology ◽

10.1085/jgp.113.2.347 ◽

1999 ◽

Vol 113 (2) ◽

pp. 347-358 ◽

Cited By ~ 70

Author(s):

Eva M. Ogielska ◽

Richard W. Aldrich

Keyword(s):

Potassium Channel ◽

Binding Site ◽

Conformational Change ◽

Electrostatic Interactions ◽

Selectivity Filter ◽

Inactivation Rate ◽

Ion Binding ◽

Present Evidence ◽

Channel Pore ◽

Functional Consequences

Ions bound near the external mouth of the potassium channel pore impede the C-type inactivation conformational change (Lopez-Barneo, J., T. Hoshi, S. Heinemann, and R. Aldrich. 1993. Receptors Channels. 1:61– 71; Baukrowitz, T., and G. Yellen. 1995. Neuron. 15:951–960). In this study, we present evidence that the occupancy of the C-type inactivation modulatory site by permeant ions is not solely dependent on its intrinsic affinity, but is also a function of the relative affinities of the neighboring sites in the potassium channel pore. The A463C mutation in the S6 region of Shaker decreases the affinity of an internal ion binding site in the pore (Ogielska, E.M., and R.W. Aldrich, 1998). However, we have found that this mutation also decreases the C-type inactivation rate of the channel. Our studies indicate that the C-type inactivation effects observed with substitutions at position A463 most likely result from changes in the pore occupancy of the channel, rather than a change in the C-type inactivation conformational change. We have found that a decrease in the potassium affinity of the internal ion binding site in the pore results in lowered (electrostatic) interactions among ions in the pore and as a result prolongs the time an ion remains bound at the external C-type inactivation site. We also present evidence that the C-type inactivation constriction is quite local and does not involve a general collapse of the selectivity filter. Our data indicate that in A463C potassium can bind within the selectivity filter without interfering with the process of C-type inactivation.

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Binding of κ-Conotoxin PVIIA to Shaker K+ Channels Reveals Different K+ and Rb+ Occupancies within the Ion Channel Pore

The Journal of General Physiology ◽

10.1085/jgp.200409048 ◽

2004 ◽

Vol 124 (1) ◽

pp. 71-81 ◽

Cited By ~ 13

Author(s):

Anna Boccaccio ◽

Franco Conti ◽

Baldomero M. Olivera ◽

Heinrich Terlau

Keyword(s):

Ion Channel ◽

Open Channel ◽

K Channel ◽

Closed Channel ◽

Channel Pore ◽

K Channels ◽

Ion Channel Pore ◽

Structural Work ◽

High K ◽

Insight Into

The x-ray structure of the KcsA channel at different [K+] and [Rb+] provided insight into how K+ channels might achieve high selectivity and high K+ transit rates and showed marked differences between the occupancies of the two ions within the ion channel pore. In this study, the binding of κ-conotoxin PVIIA (κ-PVIIA) to Shaker K+ channel in the presence of K+ and Rb+ was investigated. It is demonstrated that the complex results obtained were largely rationalized by differences in selectivity filter occupancy of this 6TM channels as predicted from the structural work on KcsA. κ-PVIIA inhibition of the Shaker K+ channel differs in the closed and open state. When K+ is the only permeant ion, increasing extracellular [K+] decreases κ-PVIIA affinity for closed channels by decreasing the “on” binding rate, but has no effect on the block of open channels, which is influenced only by the intracellular [K+]. In contrast, extracellular [Rb+] affects both closed- and open-channel binding. As extracellular [Rb+] increases, (a) binding to the closed channel is slightly destabilized and acquires faster kinetics, and (b) open channel block is also destabilized and the lowest block seems to occur when the pore is likely filled only by Rb+. These results suggest that the nature of the permeant ions determines both the occupancy and the location of the pore site from which they interact with κ-PVIIA binding. Thus, our results suggest that the permeant ion(s) within a channel pore can determine its functional and pharmacological properties.

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Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-003-0805-5 ◽

2003 ◽

Vol 368 (5) ◽

pp. 404-414 ◽

Cited By ~ 30

Author(s):

Eberhard P. Scholz ◽

Edgar Zitron ◽

Claudia Kiesecker ◽

Sonja Lueck ◽

Sven Kath�fer ◽

...

Keyword(s):

Long Qt Syndrome ◽

Drug Binding ◽

Herg Channel ◽

Antiparkinsonian Drug ◽

Long Qt ◽

Aromatic Residues ◽

Channel Pore ◽

Acquired Long Qt Syndrome ◽

Qt Syndrome

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Structural modeling of the hERG potassium channel and associated drug interactions

10.1101/2021.07.08.451699 ◽

2021 ◽

Author(s):

Jan Maly ◽

Aiyana Emigh ◽

Kevin DeMarco ◽

Kazuharu Furutani ◽

Jon T. Sack ◽

...

Keyword(s):

Potassium Channel ◽

Conformational Changes ◽

Drug Binding ◽

Selectivity Filter ◽

Herg Channel ◽

Side Chain ◽

Ion Conduction ◽

Drug Induced ◽

Channel Inactivation ◽

Conduction Pathway

The voltage-gated potassium channel, KV11.1, encoded by the human Ether-a-go-go-Related Gene (hERG) is expressed in cardiac myocytes, where it is crucial for the membrane repolarization of the action potential. Gating of hERG channel is characterized by rapid, voltage-dependent, C-type inactivation, which blocks ion conduction and is suggested to involve constriction of the selectivity filter. Mutations S620T and S641A/T within the selectivity filter region of hERG have been shown to alter the voltage-dependence of channel inactivation. Because hERG channel blockade is implicated in a number of drug-induced arrhythmias associated with both the open and inactivated states, we simulated the effects of these mutations to elucidate conformational changes associated with hERG channel inactivation and differences in drug binding between the two states. Rosetta modeling of the S641A fast-inactivating mutation revealed a lateral shift of F627 side chain in the selectivity filter into the central channel axis along the ion conduction pathway and formation of a fenestration region below the selectivity filter. Rosetta modeling of the non-inactivating mutations S620T and S641T suggested a potential molecular mechanism preventing F627 side chain from shifting into the ion conduction pathway during the proposed inactivation process. Furthermore, we used Rosetta docking to explore the binding mechanism of highly selective and potent hERG blockers - dofetilide, terfenadine, and E4031. Our results correlate well with existing experimental evidence involving interactions of these drugs with key hERG residues Y652 and F656 inside the pore and reveal potential ligand binding interactions within fenestration region in an inactivated state.

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How to Fluorescently Label the Potassium Channel: A Case in hERG

Current Medicinal Chemistry ◽

10.2174/0929867326666181129094455 ◽

2020 ◽

Vol 27 (18) ◽

pp. 3046-3054

Author(s):

Xiaomeng Zhang ◽

Beilei Wang ◽

Zhenzhen Liu ◽

Yubin Zhou ◽

Lupei Du

Keyword(s):

Potassium Channel ◽

Herg Channel ◽

Pore Channel ◽

Design Rationale ◽

Related Gene ◽

Open Conformation ◽

Cardiac Action ◽

Qt Syndrome ◽

Herg Channels ◽

Action Potential Repolarization

hERG (Human ether-a-go-go-related gene) potassium channel, which plays an essential role in cardiac action potential repolarization, is responsible for inherited and druginduced long QT syndrome. Recently, the Cryo-EM structure capturing the open conformation of hERG channel was determined, thus pushing the study on hERG channel at 3.8 Å resolution. This report focuses primarily on summarizing the design rationale and application of several fluorescent probes that target hERG channels, which enables dynamic and real-time monitoring of potassium pore channel affinity to further advance the understanding of the channels.

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